Leptin, the product of the ob gene is a hormone produced by the adipose tissue that inhibits food intake and increases energy expenditure in rodents. In humans, plasma leptin concentration correlates closely with the size of the adipose tissue depot; however, there is considerable variation in plasma leptin concentration at any given degree of fatness. Results among Pima Indians indicate that large weight gainers have relatively lower plasma leptin concentration than Pimas whose weight is stable. These data indicate that relatively low plasma leptin concentrations may play a role in the development of obesity in Pima Indians. Our studies in Pimas and Caucasians indicate: subjects with insulin resistance and hyperinsulinemia have higher plasma leptin concentration than subjects with normal insulin sensitivity; insulin acutely increases expression of leptin mRNA in the adipose tissue; menstrual abnormalities in young premenopausal women seem to occur as a consequence of the linear decline in adiposity and plasma leptin concentration in response to inadequate nutritional status. Preliminary studies indicate that subjects homozygotes for the ARG223 in the leptin receptor have lower cerebrospinal fluid leptin concentrations relative to plasma concentrations when compared to subjects heterozygous or homozygous for GLN223. This project has been terminated.